KIRs are polymorphic type 1 trans-membrane molecules present on certain subsets of lymphocytes, including NK cells and some T cells. KIRs interact with determinants in the alpha 1 and 2 domains of MHC class I molecules. In patients with AML, haplo-identical stem cell transplantation (SCT) can lead to expansion and activation of KIR-HLA class I mismatched NK cells, resulting in reduced rates of leukemia relapse, no graft-versus-host disease, and markedly improved survival rates (Ruggeri et al., Science 2002; 295:2029-31). The molecular basis for the clinical efficacy of haplo-identical SCT is that NK cell-mediated tumor killing is regulated by inhibitory KIR receptors. Upon binding to their specific HLA-B or -C ligands, these NK cell receptors transmit negative signals which inhibit NK cell-mediated killing of tumors. As HLA-B and -C molecules are highly polymorphic in the population, and distinct HLA allotypes are recognized by either KIR2DL1 or by KIR2DL2/3, it is often possible to find donors and recipients who KIR and HLA are mismatched, i.e., where the KIR of the donor do not bind an HLA ligand in the recipient. In such situations, there is no transmission of inhibitory signals via the KIR that fail to bind HLA ligands, facilitating activation of NK cells. However, this SCT protocol is not available to all patients, e.g., to the majority of AML patients who are elderly.
To achieve similar NK-mediated anti-leukemia activity by a pharmacological approach, a humanized or fully human anti-KIR antibody that is capable of blocking inhibitory KIR signalling can be used. Anti-KIR antibodies having advantageous pharmacological properties and useful in, e.g., the treatment of cancer or infectious diseases are described in WO2006003179, WO2006072626, WO2005003172, and WO2005003168. However, for clinical applications of such antibodies, optimized formulations and effective administration regimens are needed.
The invention described herein concerns formulations and administration regimens for anti-KIR antibodies, suitable for their use in promoting physiological effects useful in the treatment of cancer and other disorders or diseases.